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Learning the sequence of influenza A genome assembly during viral replication using point process models and fluorescence in situ hybridization

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  • Timothy D Majarian
  • Robert F Murphy
  • Seema S Lakdawala

Abstract

Within influenza virus infected cells, viral genomic RNA are selectively packed into progeny virions, which predominantly contain a single copy of 8 viral RNA segments. Intersegmental RNA-RNA interactions are thought to mediate selective packaging of each viral ribonucleoprotein complex (vRNP). Clear evidence of a specific interaction network culminating in the full genomic set has yet to be identified. Using multi-color fluorescence in situ hybridization to visualize four vRNP segments within a single cell, we developed image-based models of vRNP-vRNP spatial dependence. These models were used to construct likely sequences of vRNP associations resulting in the full genomic set. Our results support the notion that selective packaging occurs during cytoplasmic transport and identifies the formation of multiple distinct vRNP sub-complexes that likely form as intermediate steps toward full genomic inclusion into a progeny virion. The methods employed demonstrate a statistically driven, model based approach applicable to other interaction and assembly problems.Author summary: Influenza virus consists of eight viral ribonucleoproteins (vRNPs) that are assembled by infected cells to produce new virions. The process by which all eight vRNPs are assembled is not yet understood. We therefore used images from a previous study in which up to four vRNPs had been visualized in the same cell to construct spatial point process models that measure how well the subcellular distribution of one vRNP can be predicted from one or more other vRNPs. We used the likelihood of these models as an estimate of the extent of association between vRNPs and thereby constructed likely sequences of vRNP assembly that would produce full virions. Our work identifies the formation of multiple distinct vRNP sub-complexes that likely form as intermediate steps toward production of a virion. The results may be of use in designing strategies to interfere with virus assembly. We also anticipate that the approach may be useful for studying other assembly processes, especially for complexes with modest affinities and more components than can be visualized simultaneously.

Suggested Citation

  • Timothy D Majarian & Robert F Murphy & Seema S Lakdawala, 2019. "Learning the sequence of influenza A genome assembly during viral replication using point process models and fluorescence in situ hybridization," PLOS Computational Biology, Public Library of Science, vol. 15(1), pages 1-20, January.
  • Handle: RePEc:plo:pcbi00:1006199
    DOI: 10.1371/journal.pcbi.1006199
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    References listed on IDEAS

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    1. Jia-Ren Lin & Mohammad Fallahi-Sichani & Peter K. Sorger, 2015. "Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method," Nature Communications, Nature, vol. 6(1), pages 1-7, December.
    2. Takeshi Noda & Hiroshi Sagara & Albert Yen & Ayato Takada & Hiroshi Kida & R. Holland Cheng & Yoshihiro Kawaoka, 2006. "Architecture of ribonucleoprotein complexes in influenza A virus particles," Nature, Nature, vol. 439(7075), pages 490-492, January.
    3. Isabel Fernández de Castro Martin & Guillaume Fournier & Martin Sachse & Javier Pizarro-Cerda & Cristina Risco & Nadia Naffakh, 2017. "Influenza virus genome reaches the plasma membrane via a modified endoplasmic reticulum and Rab11-dependent vesicles," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    4. Takeshi Noda & Yukihiko Sugita & Kazuhiro Aoyama & Ai Hirase & Eiryo Kawakami & Atsuo Miyazawa & Hiroshi Sagara & Yoshihiro Kawaoka, 2012. "Three-dimensional analysis of ribonucleoprotein complexes in influenza A virus," Nature Communications, Nature, vol. 3(1), pages 1-6, January.
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